Project Summary Despite recent technological advances, on-treatment imaging for radiotherapy procedures is still a significant challenge for tens of thousands of patients. On-board MRI or kV x-ray systems are either prohibitively expensive, provide incomplete information, or are incompatible with implanted metal devices. According to the American College of Radiology, megavoltage (MV) volumetric imaging has a clear advantage in terms of metal artifact reduction, direct dose calculation and real-time adaptive radiotherapy, but is challenged by low contrast and high imaging doses. We have demonstrated that this limitation can be overcome by a novel multi-layer imager to provide high-contrast, low-dose on-treatment MV imaging. This new technology will remove metal artifacts while retaining soft-tissue contrast and enable real-time adaptive radiotherapy. We have invented and validated a Monte Carlo-based tool that enables accurate image simulation in a fraction of the time required for conventional Monte Carlo simulation ? enabling efficient imager optimization to be performed. Our preliminary data with a novel low-cost scintillator and efficient layering combinations has already demonstrated low- dose/high-quality MV-CBCT, rivaling conventional kV-CBCT, with added benefits of artifact reduction and Hounsfield unit accuracy. The Specific Aims of the current proposal will leverage our combined experience and previous results to produce an optimized imager suitable for widespread clinical use. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page